Reprogramming the Tumor Microenvironment and Translational Challenges of Immunotherapy in Gynecologic Cancers

Gynecologic cancers, including ovarian, endometrial, and cervical malignancies, represent a major burden in women’s health worldwide. Despite advances in surgery, chemotherapy, and targeted therapies, long-term survival in advanced disease, particularly in ovarian cancer, remains dismal. Immunotherapy has emerged as a transformative approach in oncology, offering durable responses in several solid tumors. However, in gynecologic cancers, its clinical impact remains limited, with few approved strategies and significant translational hurdles.To date, immune checkpoint inhibitors (ICIs) targeting programmed death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved in selected gynecologic malignancies. For instance, pembrolizumab has shown efficacy in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) endometrial cancers, and in recurrent cervical cancer with PD-L1 expression. However, in high-grade serous ovarian cancer (HGSOC), which constitutes the majority of ovarian cancer cases, no immunotherapy has yet demonstrated sufficient efficacy to gain regulatory approval. The immunosuppressive tumor microenvironment (TME), characterized by poor T cells infiltration, regulatory T cells, myeloid-derived suppressor cells, and inhibitory cytokine profiles, plays a central role in immune evasion and treatment resistance.This Research Topic focuses on reprogramming the tumor microenvironment to overcome immune resistance and enhance the efficacy of immunotherapeutic strategies in gynecologic cancers. A promising area of investigation is dual immune checkpoint blockade, particularly the combined inhibition of PD-1/PD-L1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT). TIGIT is an inhibitory receptor expressed on T cells and natural killer (NK) cells, and its blockade can restore anti-tumor immunity, especially when combined with PD-1/PD-L1 inhibition. Early-phase clinical trials are underway to assess the safety and efficacy of these combinations in solid tumors, including gynecologic malignancies.The translational challenges in this field are substantial. These include heterogeneity of the immune landscape across tumor types, clinicopathological characteristics of patients, lack of robust predictive biomarkers, difficulty in modeling human TME, and limited access to fresh tissue for immunophenotyping. Addressing these barriers requires integrative approaches, i.e. combining advanced immunoprofiling (e.g., spatial transcriptomics, single-cell RNA-seq), patient-derived models (including organoids and xenografts), and rationally designed clinical trials.This Research Topic brings together original research articles and comprehensive reviews that explore emerging immunotherapeutic strategies, dissect the complexity of the gynecologic TME, and present innovative tools to facilitate translation into clinical practice. Our goal is to foster a deeper understanding of immune-tumor interactions in gynecologic cancers and identify actionable targets for effective, personalized immunotherapy. Topic editors: IWONA WERTEL, Anna Pawłowska-Łachut, Roman Paduch Source: https://www.frontiersin.org/research-topics/73259/reprogramming-the-tumor-microenvironment-and-translational-challenges-of-immunotherapy-in-gynecologic-cancers